Amyotrophic Lateral Sclerosis (“ALS”), also known as Lou Gehrig's disease, is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, culminating in muscle wasting and death from respiratory failure (Boillee, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39-59, 2006). The majority of ALS cases are apparently sporadic, with 90% of patients presenting disease symptoms without a family history of ALS. The remaining 10% of ALS patients are diagnosed with familial ALS (Boillee et al., 1996; Brown, R. H., Jr. Amyotrophic lateral sclerosis. Insights from genetics. Arch Neurol 54, 1246-50, 1997; Cole, N. & Siddique, T. Genetic disorders of motor neurons. Semin Neurol 19, 407-18, 1999). Approximately 25% of the familial cases of ALS are caused by dominant mutations in the gene encoding super oxide dismutase (SOD1) (Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59-62, 1993). Identification of pathogenic alleles of SOD1 has led to the production of transgenic mouse and rat models for the study of ALS (Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264, 1772-5, 1994; Nagai, M. et al. Rats expressing human cytosolic copper-zinc superoxide dismutase transgenes with amyotrophic lateral sclerosis: associated mutations develop motor neuron disease. J. Neurosci. 21, 9246-54, 2001; Bruijn, L. I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327-38, 1997; Wong, P. C. et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105-16, 1995). Overproduction of pathogenic human SOD1 protein in mice and rats leads to late onset, progressive neurodegenerative disease (Gurney et al., 1994; Bruijn et al., 1997; Wong et al., 1995). Studies of the SOD1 animal models have led to the identification and study of intrinsic pathogenic characteristics of ALS motor neurons including the formation of protein aggregates, cytoskeletal abnormalities, proteosome dysfunction and increased sensitivity to cell death signals (Boillee et al., 2006; Bruijn, L. I., Miller, T. M. & Cleveland, D. W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27, 723-49, 2004).
Studies of chimeric mice suggest that non-cell autonomous processes contribute to motor neuron death in ALS (Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113-7, 2003). In animals bearing both wild-type cells and cells harboring the SOD1G93A transgene, wild-type neurons surrounded by transgenic non-neuronal cells acquired cellular phenotypes characteristic of ALS (Clement et al., 2003). Conversely, transgenic neurons associated with wild-type non-neuronal cells were increasingly spared. However, these animal studies did not identify which cells were involved in the pathological interactions with motor neurons due to the complex cellular milieu of both the spinal chord and the muscle. Conditional mutagenesis experiments in which the SOD1 transgene was specifically removed from motor neurons and microglial cells led to an increase in animal lifespan, again suggesting the SOD1 protein can have both cell autonomous and non-cell autonomous affects in the disease (Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-92, 2006). However, these experiments could not address the direct effect of cellular interactions with motor neurons in the disease because of the use of death as an endpoint.